title: Aberrant Rac1-mineralocorticoid receptor pathways in salt-sensitive hypertension.
abstract: According to Guyton's model, impaired renal sodium excretion plays a key role in the increased salt sensitivity of blood pressure (BP). Several factors contribute to impaired renal sodium excretion, including the sympathetic nervous system, the renin-angiotensin system and aldosterone. Accumulating evidence suggests that abnormalities in aldosterone and its receptor (i.e. the mineralocorticoid receptor (MR)) are involved in the development of salt-sensitive (SS) hypertension. Patients with metabolic syndrome often exhibit hyperaldosteronism and are susceptible to SS hypertension. Aldosterone secretion from the adrenal glands is not suppressed in obese hypertensive rats fed a high-salt diet because of the abundant production of adipocyte-derived aldosterone-releasing factors, which are independent of the negative feedback regulation of aldosterone secretion by the renin-angiotensin-aldosterone system. Increased plasma aldosterone levels lead to SS hypertension via MR activation in the kidney. Renal MR activity is increased in Dahl salt-sensitive rats fed a high-salt diet, despite the appropriate suppression of plasma aldosterone levels. In this rat strain, activation of MR in the distal nephron causes salt-induced hypertension. This paradoxical response of the MR to salt loading can be attributed to activation of Rac1, a small GTPase. In the presence of aldosterone, activated Rac1 synergistically and directly activates MR in a ligand-independent manner. Thus, Rac1 activation in the kidney determines the salt sensitivity of BP. Together, the available evidence suggests that the aberrant Rac1-MR pathway plays a key role in the development of SS hypertension.
authors.affiliation: Division of Clinical Epigenetics, Research Center for Advanced Science and Technology=1, The University of Tokyo=1, Tokyo, Japan.
authors.forename: Wakako
authors.initials: W
authors.lastname: Kawarazaki
authors.forename: Toshiro
authors.initials: T
authors.lastname: Fujita
mesh_terms: D000450:Aldosterone / Q000097:blood / Q000378:metabolism; D000818:Animals; D006801:Humans; D006973:Hypertension / Q000097:blood / Q000209:etiology / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism*; D024821:Metabolic Syndrome / Q000097:blood / Q000209:etiology / Q000378:metabolism*; D051381:Rats; D018161:Receptors, Mineralocorticoid / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000502:physiology; D015398:Signal Transduction; D012964:Sodium / Q000378:metabolism; D017673:Sodium Chloride, Dietary / Q000009:adverse effects*; D013564:Sympathetic Nervous System / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
chemical_list: C107953:RAC1 protein, human; D018161:Receptors, Mineralocorticoid; D017673:Sodium Chloride, Dietary; D000450:Aldosterone; D012964:Sodium; D020830:rac1 GTP-Binding Protein
keywords: Rac1; aldosterone; aldosterone-releasing factors; kidney; metabolic syndrome; mineralocorticoid receptor; obesity; salt sensitivity of blood pressure; salt-sensitive hypertension